Thursday, July 19, 2012
Box 1. Honing in on
A McMaster University team led by Mick Bhatia
has used a human pluripotent stem cell (hPSC) line that reproduces neoplastic
properties of somatic cancer stem cells14 to develop a screening
platform to identify compounds able to selectively target neoplastic cells and
not normal hPSCs.15
stem cells are characterized by enhanced self-renewal with limited cellular
differentiation, which drives tumor growth. However, the lack of a robust in
vitro assay to interrogate
human cancer stem cell differentiation has made it difficult to develop
therapeutics that interrupt the process.
team set out to develop such an assay. He is professor of biochemistry and
biomedical sciences at McMaster University and director and senior scientist at
the McMaster Stem Cell and Cancer Research Institute.
used neoplastic hPSCs and normal hPSCs expressing GFP reporters to screen
compound libraries. A decrease in the reporters indicated a loss of
self-renewal and an induction of differentiation.
the screen included thioridazine, fluphenazine, prochlorperazine, rapamycin and Teva Pharmaceutical Industries Ltd.'s lestaurtinib.
fluphenazine and prochlorperazine are dopamine receptor antagonists. Rapamycin
is a mammalian target of rapamycin (mTOR; FRAP; RAFT1) inhibitor, and the tyrosine kinase inhibitor lestaurtinib is in Phase I/II testing for
next set out to validate that thioridazine could block cancer progression in
vivo. In mice,
thioridazine decreased leukemic stem cell engraftment compared with vehicle.
a 2,446-compound library, our screening platform provided us with 26 possible
hits, with thioridazine being attractive to us because it exhibited the lowest
EC50 in neoplastic stem cells without affecting normal stem cells
and is a known antipsychotic with FDA approval," said Bhatia. "Although
our library didn't contain trifluoperazine itself-Narla's hit-our screen did
identify a couple of trifluoperazine analogs as potential anticancer
He added, "I
think our screening platform is very amenable for identifying anticancer
therapeutics. Typical assays show if compounds affect cancerous stem cells"
but do not show what happens to normal cells. "Our platform can inform you
if a compound will affect only neoplastic cells and spare normal cells."
McMaster University has mature provisional patents for the screening
technology, which is licensed to Actium Research Inc.